Socioeconomic and Demographic Disparities in Immunotherapy Utilization for Advanced Kidney and Bladder Cancer.

OBJECTIVES: Immunotherapy (IO) drugs have been increasingly utilized in locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma of the bladder (UC). Multiple trials have demonstrated clear survival benefit, however, there are often barriers to access for these advanced therapies which has been demonstrated in other non-urologic malignancies. The goal of this study was to assess socioeconomic and demographic factors associated with the receipt of IO for advanced ccRCC and UC. MATERIALS AND METHODS: We queried the National Cancer Database (NCDB) for patients with stage IV ccRCC and UC. The study period was 2015 to 2020 for ccRCC (FDA approval date of IO) and 2017 to 2020 for UC (FDA approval date of broadened indication for IO, initial limited approval in 2016). The primary outcome of interest was receipt of IO therapy using multivariable logistic regression, adjusting for relevant socioeconomic and demographic variables. RESULTS: We identified 15,926 patients with stage IV ccRCC and 10,380 patients with stage IV UC of which 5,419 (34.0%) and 2,231 (21.5%) received IO therapy, respectively. IO utilization increased with each successive year. In both malignancies, treatment at a non-academic facility, education level, income, and insurance were independently associated with IO utilization. For ccRCC, black (OR = 0.77, 95% CI, 0.64-0.93, P = 0.009) and Hispanic race (OR = 0.73, 95% CI, 0.61-0.86, P = 0.006) were each associated with decreased IO utilization but there were no independent associations between race and receipt of IO in patients with UC. CONCLUSIONS: In the era of FDA-approved IO therapy for advanced ccRCC and UC, this national cohort analysis suggests that IO utilization is increasing over time, but significant disparities exist based on income, education, and insurance status in both malignancies. Additionally, patients treated at non-academic facilities were less likely to receive IO therapy for these specific genitourinary malignancies. In ccRCC, additional disparities were seen black and Hispanic races which each were associated with lower odds of IO receipt. Identifying strategies to mitigate these differences and provide equitable access to IO therapy is of imperative need.

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Differences in systemic immune parameters in individuals with lung cancer according to race.

Introduction: Racial and ethnic disparities in the presentation and outcomes of lung cancer are widely known. To evaluate potential factors contributing to these observations, we measured systemic immune parameters in Black and White patients with lung cancer. Methods: Patients scheduled to receive cancer immunotherapy were enrolled in a multi-institutional prospective biospecimen collection registry. Clinical and demographic information were obtained from electronic medical records. Pre-treatment peripheral blood samples were collected and analyzed for cytokines using a multiplex panel and for immune cell populations using mass cytometry. Differences between Black and White patients were determined and corrected for multiple comparisons. Results: A total of 187 patients with non-small cell lung cancer (Black, 19; White, 168) were included in the analysis. There were no significant differences in baseline characteristics between Black and White patients. Compared to White patients, Black patients had significantly lower levels of CCL23 and CCL27, and significantly higher levels of CCL8, CXCL1, CCL26, CCL25, CCL1, IL-1 b, CXCL16, and IFN-γ (all P <0.05, FDR<0.1). Black patients also exhibited greater populations of non-classical CD16+ monocytes, NKT-like cells, CD4+ cells, CD38+ monocytes, and CD57+ gamma delta T cells (all P <0.05). Conclusions: Black and White patients with lung cancer exhibit several differences in immune parameters, with Black patients exhibiting greater levels of numerous pro-inflammatory cytokines and cell populations. The etiology and clinical significance of these differences warrant further evaluation.

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy.

BACKGROUND AND OBJECTIVE: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. METHODS: Patients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, 6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%,

Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease.

BACKGROUND: IL-17A plays a pivotal pathogenic role in several immune-mediated inflammatory diseases. Despite sharing 50% sequence homology with IL-17A, the role of IL-17F remains less clear. Clinical findings suggest that dual inhibition of IL-17A and IL-17F in psoriatic disease is more efficacious than IL-17A inhibition alone, positing a pathogenic role for IL-17F. OBJECTIVE: We characterized the regulation of IL-17A and IL-17F in psoriatic disease. METHODS: Using both in vitro systems and lesional skin tissue from patients, we interrogated the chromosomal, transcriptional, and protein expression landscape of IL-17A+ and IL-17F+ TH17 cells. Alongside established assays such as single-cell RNA sequencing, we developed a novel cytokine-capture technique that was combined with chromatin immunoprecipitation sequencing and RNA sequencing. RESULTS: We confirm a preferential elevation of IL-17F over IL-17A in psoriatic disease and show that expression of each isoform predominantly occurs in distinct cell populations. The expression of both IL-17A and IL-17F exhibited a high degree of plasticity, with the balance between the 2 isoforms influenced by proinflammatory signaling and by anti-inflammatory drugs such as methylprednisolone. This plasticity was reflected in a broad H3K4me3 region at the IL17A-F locus, while opposing effects of STAT5/IL-2 signaling were observed for each of the 2 genes. Functionally, higher IL17F expression was linked to greater cell proliferation. CONCLUSION: There are key differences in the regulation of IL-17A and IL-17F in psoriatic disease, leading to distinct inflammatory cell populations. As such, we propose that both IL-17A and IL-17F neutralization may be required to maximally inhibit IL-17-driven pathology.

Colorectal cancer metastases in thyroid: case report and literature review.

BACKGROUND: The thyroid gland is an uncommon site for metastatic deposits from non-thyroid malignancies, occurring in only 1.4 - 3% of surgical specimens where malignancy is suspected. It is even rarer for the source of thyroid metastases to be of colorectal origin. In most cases reported, colorectal metastases in the thyroid occurs many years later after the primary colorectal cancer has been diagnosed and treated. In this unique case, a primary sigmoid carcinoma metastasised to the thyroid gland and presented synchronously as a thyroid nodule. CASE PRESENTATION: We describe a case of a 64-year-old Caucasian woman who presented with clinical features of metastatic cancer of unknown origin. Her medical history included underlying hyperthyroidism. She had a large pelvic mass adjacent to the sigmoid colon, a left lower lobe lung mass and a suspicious nodule in the left thyroid lobe. A fine-needle aspiration biopsy of the thyroid nodule was performed, which remarkably showed malignant cells originating from primary colorectal cancer on immunohistochemical staining. The patient was managed with palliative chemotherapy given the poor prognosis due to disseminated colorectal malignancy. CONCLUSIONS: Colorectal adenocarcinoma metastases can rarely present as a metastatic thyroid nodule. Fine-needle aspiration should be performed in suspicious thyroid nodules and may be the least invasive way of identifying a metastatic colorectal or other non-thyroidal malignancy in patients presenting with an unknown primary. The pathologist should be vigilant to this possibility and specific immunohistochemical markers should be used to ensure accurate diagnosis. In thyroid metastases, the prognosis is ultimately determined by the primary tumour but thyroidectomy still has a role in alleviating compressive symptoms and can potentially improve survival in selected cases.

Actionable genomic landscapes from a real-world cohort of urothelial carcinoma patients.

BACKGROUND: Recent targeted therapies for advanced and metastatic urothelial cancer have generated enthusiasm, but the actionable genomic landscape of early-stage disease remains largely unknown. Here, we utilized a large, real-world cohort to comprehensively investigate the incidence of genetic alterations with potential therapeutic implications at all stages of bladder cancer. MATERIALS AND METHODS: We retrospectively analyzed next-generation sequencing (NGS) data from 1,562 bladder cancer patients (stages I-IV) with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus xT solid tumor assay. Incidence of genetic alterations, tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 status were assessed and stratified by bladder cancer stage. For patients with tumor-normal match sequencing (n=966), incidental germline alterations in 50 genes were assessed. RESULTS: The cohort was composed of 165 stage I-II, 211 stage III, and 1,186 stage IV tumors. TMB-high, PD-L1 positive, and MSI-high status were noted in 14%, 33%, and 0.7% of tumors, respectively, and were similar across stages. Alterations in fibroblast growth factor receptor (FGFR)2/3, homologous recombination repair genes, additional DNA repair gene mutations (ERCC2, RB1, FANCC), and NTRK fusions were detected at similar frequencies across disease stages. We identified a low rate of incidental germline mutations in all tumors (5.2%) and in specific genes: MUTYH (1.9%), BRCA2 (0.5%), and ATM (0.8%). CONCLUSIONS: Important subsets of patients demonstrate genetic alterations in potentially actionable molecular pathways at all stages. This analysis found minimal variability in these alterations across stages, providing rationale for early identification of genetic alterations and personalization of therapies at all stages for patients with bladder cancer.

Iron Screening in Alopecia Areata Patients May Catch Hereditary Hemochromatosis Early.

Hereditary hemochromatosis (HHC), a disorder of iron overload, presents with clinical phenotypic heterogeneity. Complications can be mitigated with early intervention. The association between HHC and alopecia areata (AA) is unknown. We report 4 patients with HHC concurrent with AA. In 2 patients, the HHC diagnosis was revealed from the results of laboratory iron studies as part of an alopecia consultation workup. Alopecia areata may be a rare early cutaneous manifestation of HHC in individuals with a predisposition for autoimmunity; however, the genetic relationship between the 2 disorders is currently unknown. Patients at high risk for HHC such as those with a family history and/or those who fit the demographic profile may benefit from laboratory iron screening if they present to the clinic with AA.

Stereotactic Ablative Radiation for Systemic Therapy-naïve Oligometastatic Kidney Cancer.

BACKGROUND: Evidence-based guidelines for the management of systemic therapy-naïve oligometastatic renal cell carcinoma (RCC) are lacking. OBJECTIVE: To evaluate the potential of stereotactic ablative radiotherapy (SAbR) to provide longitudinal disease control while preserving quality of life (QOL) in patients with systemic therapy-naïve oligometastatic RCC. DESIGN, SETTING, AND PARTICIPANTS: RCC patients with three or fewer extracranial metastases were eligible. SAbR was administered longitudinally to all upfront and, as applicable, subsequent metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: This prospective phase II single-arm trial was powered to achieve a primary objective of freedom from systemic therapy for >1 yr in >60% of patients (using the Clopper and Pearson methodology). Secondary endpoints included progression-free survival (PFS), defined as the time from first SAbR to progression not amenable to SAbR (local failure at SAbR-treated sites, new metastases not amenable to SAbR, more than three new metastases, or brain metastases); patient-reported QOL metrics; local control (LC) rates; toxicity; cancer-specific survival (CSS); and overall survival (OS). RESULTS AND LIMITATIONS: Twenty-three patients received SAbR to 33 initial and 57 total sites. The median follow-up was 21.7 mo (interquartile range 16.3-30.3). Exceeding the prespecified 60% benchmark, freedom from systemic therapy at 1 yr was 91.3% (95% confidence interval [CI]: 69.5, 97.8). One-year PFS was 82.6% (95% CI: 60.1, 93.1). QOL was largely unaffected. LC was 100%. There were no grade 3/4 toxicities, but there was one death due to immune-related colitis 3 mo after SAbR while on subsequent checkpoint inhibitor therapy, where a SAbR contribution could not be excluded. One-year OS was 95.7% (95% CI: 72.9, 99.4); one-year CSS was 100%. CONCLUSIONS: SAbR for oligometastatic RCC was associated with meaningful longitudinal disease control while preserving QOL. These data support further evaluation of SAbR for systemic therapy-naïve oligometastatic RCC. PATIENT SUMMARY: Sequential stereotactic radiation therapy can safely and effectively control metastatic kidney cancer with limited spread for over a year without compromising patients' quality of life.

Severe Cholestatic Jaundice (Stauffer Syndrome) as a Rare Paraneoplastic Manifestation in Adrenocortical Carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. While ACC can be associated with adrenal hormone excess syndromes, classic paraneoplastic syndromes are rarely seen. Stauffer syndrome, a paraneoplastic phenomenon characterized by reversible cholestasis in the absence of liver metastases, has been described with renal carcinoma and other malignancies but has not been previously reported in ACC. Case Presentation: A 38-year-old man presented with emesis, painless jaundice, pruritus, and weight loss. Laboratory evaluation demonstrated elevated total bilirubin of 8.7 mg/dL (N < 1.3 mg/dL). Computed tomography revealed a 20.4-cm left adrenal mass without evidence of liver metastases. The patient's condition deteriorated rapidly with progressive renal failure and worsening hyperbilirubinemia. The patient underwent left adrenalectomy, nephrectomy, ureterolysis, and wedge liver biopsy. Histopathology showed necrotic ACC with tumor invasion into the adrenal capsule, no lymphovascular invasion, uninvolved margins, and Ki-67 of 40%. Kidney parenchyma exhibited diffuse pigment casts. The liver specimen contained diffuse bile deposits and minimal chronic inflammation in the portal tracts. He tested positive for the pathogenic variant of folliculin (FLCN) gene consistent with Birt-Hogg-Dube syndrome. Renal function recovered after surgery, and bilirubin level normalized after several weeks. Based on clinical presentation and absence of other etiologies, reversible cholestatic jaundice was attributed to Stauffer syndrome. Conclusion: This is the first report of a unique presentation of paraneoplastic-related hyperbilirubinemia in the setting of ACC. While extremely rare, Stauffer syndrome should still be considered in differential diagnosis in patients with ACC with liver dysfunction and jaundice without evidence of liver metastases.

Serologic Biomarkers of Progression Toward Diagnosis of Rheumatoid Arthritis in Active Component Military Personnel.

OBJECTIVE: To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis. METHODS: Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase. RESULTS: Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%). CONCLUSION: Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis.

Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis.

OBJECTIVES: Immune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation. METHODS: Single cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters. RESULTS: Global transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor-ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-ß and macrophage interleukin (IL)-1ß synergy in driving the transcriptional profile of FAPα+THY1+ invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-ß and IL-1ß treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.

Targeting FGFR3 alterations with adjuvant infigratinib in invasive urothelial carcinoma: the phase III PROOF 302 trial.

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1-21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

Cancers of the bladder and other parts in the urinary system, especially those that are invasive and grow into the muscle layer, may need extra treatment after surgical removal of the tumor, particularly if there is a high risk of the cancer coming back. Chemotherapy regimens that include cisplatin are often used postoperatively, although some patients are unable to tolerate this treatment or refuse it. FGFR3, a protein that is encoded by the FGFR3 gene, is often changed in these cancers. This helps the tumor grow. Infigratinib is an investigational drug that targets FGFR3 and inhibits the abnormal growth of the tumor. In the PROOF 302 study, patients are randomly assigned to treatment with infigratinib or a placebo pill for 1 year after surgery to see if the drug is effective. The aim is to see if patients who take infigratinib have a longer time free from the disease than those who receive a placebo. The study will also look at how long patients remain free from cancer spread and how long they live overall. The study will also investigate how safe the treatment is and how easy it is to live with it. PROOF 302 is an important study as it will define the role of infigratinib in patients with cancers of the bladder and urinary system who also have FGFR3 changes, for whom more treatment choices are needed. Clinical Trial Registration: NCT04197986 (ClinicalTrials.gov).

The impact of race and ethnicity on outcomes of patients with myelodysplastic syndromes: a population-based analysis.

Race and ethnic backgrounds affect the disease characteristics and clinical outcomes in many cancers, including acute myeloid leukemia; however, the association of race/ethnicity on myelodysplastic syndrome (MDS) is still controversial. Therefore, we aimed to study the impact of race/ethnicity on the disease characteristics and survival outcomes in patients with MDS. Adult patients with MDS diagnosed in 2004-2016 were selected using the SEER database. Race/ethnicity was categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic. Hispanic and NHB patients had significantly lower incidence rate ratio (IRR) in age group ≥01 years (p < .001) compared to NHW; however, in the age group <50 years, NHB patients had significantly higher IRR with an increased incidence rate of 49%. NHB patients had better overall survival than Hispanic and NHW patients (p < .001), even after adjusting for confounding variables. MDS have significant differences in age at diagnosis, disease risk, and survival outcomes based on racial/ethnic backgrounds.

Attenuation of the BTLA/HVEM Regulatory Network in the Circulation in Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (SjS) is an inflammatory autoimmune disorder which targets the lacrimal and salivary glands, resulting in glandular dysfunction. Currently, the immune drivers of SjS remain poorly understood and peripheral biomarkers of disease are lacking. The present study therefore sought to investigate the immune cell constituents of the SjS peripheral blood, and to assess the role of the BTLA/HVEM/CD160 co-stimulatory network by characterizing expression within the periphery. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of n = 10 patients with SjS and n = 10 age- and sex-matched healthy control donors. Cells were divided and stained with three panels of antibodies, allowing assessment of T, B, and myeloid cell subsets, and measurement of BTLA, HVEM, and CD160 surface expression by flow cytometry. We identified distinct alterations in proportions of peripheral T, B, and myeloid cell types in SjS compared with healthy controls. Expression of BTLA/CD160/HVEM and frequency of BTLA/CD160/HVEM-expressing cells were significantly altered in peripheral SjS lymphocytes. The proportion of T cells co-expressing BTLA/HVEM and CD160/HVEM were significantly reduced in SjS. We found decreased BTLA and HVEM levels on peripheral B and T cells of SjS patients, and decreased BTLA/HVEM and CD160/HVEM co-expression, demonstrating dysregulation of the BTLA/HVEM axis in the peripheral blood of SjS patients. These results indicate the potential of targeting the BTLA-HVEM axis for the treatment of SjS.

Phase II Trial of Stereotactic Ablative Radiation for Oligoprogressive Metastatic Kidney Cancer.

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) treated with systemic therapy sometimes progress at limited sites.The best treatment approach for patients with oligoprogression remains unclear. OBJECTIVE: To determine the ability of stereotactic ablative radiation (SAbR) to extend ongoing systemic therapy in mRCC patients with oligoprogression. DESIGN, SETTING, AND PARTICIPANTS: A single-arm phase II clinical trial was conducted at a university medical center and county hospital, including 20 patients with mRCC on first- to fourth-line systemic therapy with three or fewer sites of progression (including new sites) involving ≤30% of all sites. INTERVENTION: SAbR to oligoprogressing metastases at outset and longitudinally, while radiated sites remain controlled and overall disease oligoprogressive. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was to extend ongoing systemic therapy by >6 mo in >40% of patients. Secondary endpoints included overall survival, toxicity, and patient-reported quality of life. RESULTS AND LIMITATIONS: Twenty patients were enrolled. Upfront and sequential SAbR was administered to a total of 37 sites. The local control rate was 100%. At a median follow-up of 10.4 mo (interquartile range: 5.8-16.4), SAbR extended the duration of the ongoing systemic therapy by >6 mo in 14 patients (70%, 95% confidence interval [CI]: 49.9-90.1). The median time from SAbR to the onset of new systemic therapy or death was 11.1 mo (95% CI: 4.5-19.3). The median duration of SAbR-aided systemic therapy was 24.4 mo (95% CI: 15.3-42.2). Median overall survival was not reached. One patient developed grade 3 gastrointestinal toxicity possibly related to treatment. There was no significant decline in quality of life. Limitations include nonrandomized design and a small patient cohort. CONCLUSIONS: SAbR extended the duration of the ongoing systemic therapy for patients with oligoprogressive mRCC without undermining quality of life. These data support the evaluation of SAbR for oligoprogressive mRCC in a prospective randomized clinical trial. PATIENT SUMMARY: Patients with metastatic kidney cancer on systemic therapy but progressing at limited sites may benefit from focused radiation to progressive sites. Focused radiation was safe and effective, and extended the duration of the ongoing systemic therapy.

Women Oncologists' Perceptions and Factors Associated With Decisions to Pursue Academic vs Nonacademic Careers in Oncology.

Importance: Women outnumber men in US medical school enrollment, but they represent less than 40% of academic oncology faculty. Objective: To identify the key factors associated with female oncologists' decision to pursue academic or nonacademic oncology practice and to characterize their perceptions about their current career. Design, Setting, and Participants: This cross-sectional survey study was distributed through email and social media to female physicians in academic and nonacademic oncology practice in the United States. The survey was open for 3 months, from August 1 to October 31, 2020. Main Outcomes and Measures: No single primary study outcome was established because of the cross-sectional nature of the survey. Data were collected anonymously and analyzed using t tests for continuous variables and χ2 tests for categorical variables. Results: Among the 667 female respondents, 422 (63.2%) identified as academic oncologists and 245 (36.8%) identified as nonacademic oncologists. Approximately 25% of respondents reported that their spouse or partner (156 [23.5%]) and/or family (176 [26.4%]) extremely or moderately affected their decision to pursue academic practice. Academic oncologists perceived the biggest sacrifice of pursuing academics to be time with loved ones (181 [42.9%]). Nonacademic oncologists perceived the biggest sacrifice of pursuing academics to be pressure for academic promotion (102 [41.6%]). Respondents had different perceptions of how their gender affected their ability to obtain a chosen job, with 116 academic oncologists (27.6%) and 101 nonacademic oncologists (41.2%) reporting a positive or somewhat positive impact (P = .001). More than half of the women surveyed (54.6% academic oncologists [230]; 50.6% nonacademic oncologists [123]; P = .61) believed they were less likely to be promoted compared with male colleagues. Academic and nonacademic oncologists reported rarely or never having a sense of belonging in their work environment (33 [7.9%] and 5 [2.0%]; P < .001). Most respondents reported that they would choose the same career path again (301 academic oncologists [71.3%]; 168 nonacademic oncologists [68.6%]); however, 92 academic oncologists (21.9%) reported they were likely to pursue a career outside of academic oncology in the next 5 years. Conclusions and Relevance: This survey study found that a spouse or partner and/or family were factors in the career choice of both academic and nonacademic oncologists and that female gender was largely perceived to adversely affect job promotion. Given that more than 20% of female academic oncologists were considering leaving academia, gender inequality is at high risk of continuing if the culture is not addressed.

Stereotactic Ablative Radiation Therapy for Oligoprogressive Renal Cell Carcinoma.

PURPOSE: Oligoprogression, defined as limited sites of progression on systemic therapy, in patients with metastatic renal cell carcinoma (mRCC) is not uncommon, possibly because of inter- and intratumoral heterogeneity. We evaluated the effect of stereotactic ablative radiation therapy (SAbR) for longitudinal control of oligoprogressive mRCC. METHODS AND MATERIALS: Patients with extracranial mRCC were included in this retrospective analysis if they progressed in ≤3 sites on systemic therapy while demonstrating response/stability at other sites and received SAbR to all progressing sites without switching systemic therapy. Our primary endpoint was modified progression-free survival (mPFS), which we calculated from the start of SAbR to the start of a subsequent systemic therapy, death, or loss to follow-up. RESULTS: We identified 36 patients with a median follow-up of 20.4 months (interquartile range, 10.9-29.4). Forty-three sites were treated with SAbR with a median dose of 36 Gy (range, 18-50) in 3 fractions (range, 1-5). Median time to SAbR from the start of systemic therapy was 11.4 months (interquartile range, 6.1-17.1). Median mPFS was 9.2 months (95% confidence interval [CI], 5.9-13.2). Patients receiving SAbR while on immunotherapy exhibited a longer median mPFS (>28.4 months, log-rank P = .0001) than patients not on immunotherapy (9.2 months). Median overall survival from SAbR administration was 43.4 months (95% CI, 21.5-not Reached). The 1-year local control rate was 93% (95% CI, 78.7-97.5). Most SAbR-related toxicities were grade 1 to 2 (33% of patients), with one grade 5 hemoptysis event possibly related to SAbR or disease progression. CONCLUSIONS: SAbR has the potential to extend the the duration of current systemic therapy for selected patients with mRCC, preserving subsequent therapies for later administration possibly enabling longer treatment duration.

Ex vivo mass cytometry analysis reveals a profound myeloid proinflammatory signature in psoriatic arthritis synovial fluid.

OBJECTIVES: A number of immune populations have been implicated in psoriatic arthritis (PsA) pathogenesis. This study used mass cytometry (CyTOF) combined with transcriptomic analysis to generate a high-dimensional dataset of matched PsA synovial fluid (SF) and blood leucocytes, with the aim of identifying cytokine production ex vivo in unstimulated lymphoid and myeloid cells. METHODS: Fresh SF and paired blood were either fixed or incubated with protein transport inhibitors for 6 hours. Samples were stained with two CyTOF panels: a phenotyping panel and an intracellular panel, including antibodies to both T cell and myeloid cell secreted proteins. Transcriptomic analysis by gene array of key expanded cell populations, single-cell RNA-seq, ELISA and LEGENDplex analysis of PsA SF were also performed. RESULTS: We observed marked changes in the myeloid compartment of PsA SF relative to blood, with expansion of intermediate monocytes, macrophages and dendritic cell populations. Classical monocytes, intermediate monocytes and macrophages spontaneously produced significant levels of the proinflammatory mediators osteopontin and CCL2 in the absence of any in vitro stimulation. By contrast minimal spontaneous cytokine production by T cells was detected. Gene expression analysis showed the genes for osteopontin and CCL2 to be among those most highly upregulated by PsA monocytes/macrophages in SF; and both proteins were elevated in PsA SF. CONCLUSIONS: Using multiomic analyses, we have generated a comprehensive cellular map of PsA SF and blood to reveal key expanded myeloid proinflammatory modules in PsA of potential pathogenic and therapeutic importance.